The present invention relates to phytanic acid derivatives and their use for the treatment or the prevention of diabetes mellitus.
This invention relates to a novel method for the treatment or prevention of preferably non-insulin dependent (NIDDM or so-called Type II) diabetes mellitus, and in particular to the use of phytanic acid derivatives for the treatment or prevention of NIDDM.
NIDDM is the form of diabetes mellitus that occurs predominantly in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues. Overt NIDDM is characterized by three major metabolic abnormalities: elevated serum glucose levels, resistance to insulin-mediated glucose disposal, and overproduction of glucose by the liver.
Previous mechanisms of action of oral antidiabetics such as the generally used sulfonyl ureas are primarily based on an increased release of insulin from the beta cells of the pancreas, a mechanism which in the long term may lead to accelerated exhaustion of the endogenous production of insulin in diabetics. The modern view of the pathobiochemistry of adult-onset diabetes mellitus therefore emphasizes the need to treat the peripheral insulin resistance that is present in this case.
The human diet contains phytol, a metabolite of the chlorophyll molecule. Phytol is metabolized to phytenic acid and phytanic acid (see FIG. 6). Intestinal absorption of phytol from dietary chlorophyll was shown to be minimal (Baxter, J. H. and Steinberg, D. (1967) Absorption of phytol from dietary chlorophyll in the rat, J Lipid Res. 8, 615-20; Baxter, J. H. (1968) Absorption of chlorophyll phytol in normal man and in patients with Refsum""s disease, J Lipid Res. 9, 636-41).
In rats, phytol is much less well adsorbed than phytanic acid (Baxter, J. H., Steinberg, D., Mize, C. E. and Avigan, J. (1967) Absorption and metabolism of uniformly 14C-labeled phytol and phytanic acid by the intestine of the rat studied with thoracic duct cannulation, Biochim Biophys Acta. 137, 277-90).
In humans, dairy products and ruminant fats in the human diet are the major sources of phytanic acid. A normal diet contains 50-100 mg of phytanic acid per day (Steinberg. (1995) Refsum Disease in the Metabolic and Molecular Bases of Inherited Metabolic Disorders pp. 2351-2369, McGraw-Hill, New York). Phytenic- and phytanic acid levels in normal human serum were 2 xcexcM and 6 xcexcM (Avigan, J. (1966) The presence of phytanic acid in normal human and animal plasma, Biochim Biophys Acta. 116, 391-4). Phytanic acid may be elevated 50-fold in patients with heredopathia atactica polyneuritiformis (Refsum""s disease), an inherited metabolic disorder characterized by an xcex1-hydroxylase gene defect that prevents the conversion of phytanic acid to pristanic acid (Verhoeven, N. M., Wanders, R. J., Poll-The, B. T., Saudubray, J. M. and Jakobs, C. (1998) The metabolism of phytanic acid and pristanic acid in man: a review, J Inherit Metab Dis. 21, 697-728).
In adult mice fed a 0.5% phytol diet for 21 days a 40% decrease in the triglyceride serum levels was noted. However, cholesterol serum levels remained unaffected (Van den Branden, C., Vamecq, J., Wybo, I. and Roels, F. (1986) Phytol and peroxisome proliferation, Pediatr Res. 20, 411-5). Moreover, expression of enzymes, known to be involved in beta-oxidation and regulated by peroxisome proliferator-activated receptor (PPAR) was observed to be up regulated. Recently it was shown that phytanic acid is a 9-cis-retinoic acid receptor (RXR) as well as a PPARxcex1 ligand (Kitareewan, S., Burka, L. T., Tomer, K. B., Parker, C. E., Deterding, L. J., Stevens, R. D., Forman, B. M., Mais, D. E., Heyman, R. A., McMorris, T. and Weinberger, C. (1996) Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR, Molecular Biology of the Cell. 7, 1153-66.; Lemotte, P. K., Keidel, S. and Apfel, C. M. (1996) Phytanic acid is a retinoid X receptor ligand, Eur J Biochem. 236, 328-33; Wolfrum, C., Ellinghaus, P., Fobker, M., Seedorf, U., Assmann, G., Borchers, T. and Spener, F. (1999) Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein, J Lipid Res. 40, 708-14.; Ellinghaus, P., Wolfrum, C., Assmann, G., Spener, F. and Seedorf, U. (1999) Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/sterol carrier protein x-deficient mice, J Biol Chem. 274, 2766-72 and WO 97/09039).
RXR receptor binding and transcriptional effects were observed with EC50 and IC50 of 3 xcexcM and 2.3 xcexcM respectively. The Kd-value for phytanic acid as PPARxcex1 ligand is reported as 10 nM (Ellinghaus et al., supra). In contrast to the ability of 9-cis-retinoic acid to activate both RXR and all-trans-retinoic acid receptor (RAR) (EC50 2.5 nM and 13 nM), phytanic acid activity is restricted to RXR receptors. Activation of both PPARxcex1 and RXR by phytanic acid and the specificity with respect to the retinoid receptors may lead to a distinct pattern of gene induction as opposed to the pattern observed in other fatty acids.
Liver is second to skeletal muscle as the most important tissue in glucose metabolism and therefore is an important regulator of glucose level in plasma. It is well known that activation of PPARxcex3 by the antidiabetic thiazolidinediones such as troglitazone rosiglitazone and pioglitazone leads to restored insulin sensitivity in case of diabetes mellitus type II (Berger, J., Bailey, P., Biswas, C., Cullinan, C. A., Doebber, T. W., Hayes, N. S., Saperstein, R., Smith, R. G. and Leibowitz, M. D. (1996) Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice, Endocrinology. 137, 4189-95; Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M. and Kliewer, S. A. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARxcex3), J Biol Chem. 270, 12953-6.12, 13). Expression of PPARxcex1 as well as PPARxcex3 was shown in liver of rodents and humans (Mukherjee, R., Jow, L., Croston, G. E. and Paterniti, J. R., Jr. (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARxcex32 versus PPARxcex31 and activation with retinoid X receptor agonists and antagonists, J Biol Chem. 272, 8071-6.; Lemberger, T., Braissant, O., Juge-Aubry, C., Keller, H., Saladin, R., Staels, B., Auwerx, J., Burger, A. G., Meier, C. A. and Wahli, W. (1996) PPAR tissue distribution and interactions with other hormone-signaling pathways, Ann N Y Acad Sci. 804, 231-51; Palmer, C. N., Hsu, M. H., Griffin, K. J., Raucy, J. L. and Johnson, E. F. (1998) Peroxisome proliferator activated receptor-alpha expression in human liver, Mol Pharmacol. 53, 14-22. ; Vidal-Puig, A. J., Considine, R. V., Jimenez-Linan, M., Werman, A., Pories, W. J., Caro, J. F. and Flier, J. S. (1997) Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids, J Clin Invest. 99, 2416-22).
Phytanic acid was described as a ligand for both RXR and PPARxcex1 (Kitareewan, et al. (supra); Lemotte et al. (supra); Ellinghaus et al (supra) and WO97/09039). Decaux et al. (Decaux, J. F., Juanes, M., Bossard, P. and Girard, J. (1997) Effects of triiodothyronine and retinoic acid on glucokinase gene expression in neonatal rat hepatocytes, Mol Cell Endocrinol. 130, 61-7) demonstrated in primary cultures of rat hepatocytes, an up-regulation of glucokinase mRNA by retinoic acid. Together with the finding that the phosphoenolpyruvate carboxykinase (PEPCK) gene is regulated among other responsive elements by a PPAR responsive element (PPRE) (Juge-Aubry, C., Pernin, A., Favez, T., Burger, A. G., Wahli, W., Meier, C. A. and Desvergne, B. (1997) DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5xe2x80x2-flanking region, J Biol Chem. 272, 25252-9; Hanson, R. W. and Reshef, L. (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression, Annu Rev Biochem. 66, 581-611), a RXR/PPAR mediated up-regulation of the glucose influx in hepatocytes could be a reasonable explanation. PPAR forms permissive heterodimers with RXR, meaning that either partner can regulate the transcriptional activity by interacting with its own ligand. Co-treatment of the cells with ligands for PPAR as well as RXR results in an additive effect. Moreover it was shown that ligands selective for RXR could activate PPRE driven reporter genes (Kliewer, S. A., Umesono, K., Noonan, D. J., Heyman, R. A. and Evans, R. M. (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors, Nature. 358, 771-4; Gearing, K. L., Gottlicher, M., Teboul, M., Widmark, E. and Gustafsson, J. A. (1993) Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor, Proc Natl Acad Sci U S A. 90, 1440-4; Keller, H., Dreyer, C., Medin, J., Mahfoudi, A., Ozato, K. and Wahli, W. (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers, Proc Natl Acad Sci U S A. 90, 2160-4).
In vivo sensitization to insulin was observed in diabetic and obese mice in response to RXR agonists, comparable to the effects known from the thiazolidinediones (Mukherjee, R., Davies, P. J., Crombie, D. L., Bischoff, E. D., Cesario, R. M., Jow, L., Hamann, L. G., Boehm, M. F., Mondon, C. E., Nadzan, A. M., Paterniti, J. R., Jr. and Heyman, R. A. (1997) Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists, Nature. 386, 407-10).
However, there is no indication in the prior art that phytanic acid derivatives, preferably phytanic acid, would have a beneficial effect on NIDDM itself.
Surprisingly, experiments showed that phytanic acid derivatives, preferably phytanic acid, can increase and stimulate the transcription of the genes for glucose transporters and glucokinase resulting in increased glucose uptake in hepatocytes.
Moreover, phytanic acid derivatives normalize and increase the glucose level without a concomitant risk of hypoglycemia and is thus excellently suited for the treatment or prevention of diabetes mellitus.
An object of the present invention is therefore a novel method for the treatment or prevention of preferably NIDDM.
This object is achieved by the use of phytanic acid derivatives for the treatment or prevention of diabetes mellitus, preferably diabetes mellitus type II per se. In a particular embodiment the use of phytanic acid is preferred.
One embodiment of the present invention is a method of making a composition for the treatment or prevention of a disease selected from the group consisting of non-insulin dependent diabetes mellitus, syndrome X, hyperlipidaemia, hypertension, hyperinsulinaemia, hypercholesterinaemia, hypertriglycerinaemia, impaired glucose tolerance and related obesity comprising combining phytanic acid or a phytanic acid derivative with a pharmaceutically acceptable carrier.
Another embodiment of the present invention is a composition for the treatment or prevention of non-insulin dependent diabetes mellitus comprising phytanic acid or a derivative thereof.
A further embodiment of the invention is a dietary supplement comprising a composition comprising phytanic acid or a derivative thereof.
Another embodiment of the invention is a method of treating or preventing non-insulin dependent diabetes mellitus comprising administering to a human or an animal an effective dose of a pharmaceutical composition or a dietary supplement comprising phytanic acid, a phytanic acid precursor, or a derivative phytanic acid.
Another embodiment of the invention is a method for increasing cellular glucose uptake comprising administering to an animal or a human in need of increased cellular glucose uptake a phytanic acid derivative or a phytanic acid precursor in an effective amount to increase cellular glucose uptake.
Another embodiment of the invention is a method of reducing plasma insulin comprising administering to a mammal a plasma insulin reducing amount of a composition comprising phytanic acid or a derivative thereof.
In the present invention, the following abbreviations are used: Apolipoprotein A1 (ApoA1) and Apolipoprotein E (ApoE), cytochrome P450/4A1 (Cyp4a1), cholesterol 7xcex1-hydroxylase and glucokinase (Cyp7a), docohexaenoic acid (DHA), facilitative glucose transporter (GLUT), 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)-reductase, lipoprotein lipase (LPL), low-density lipoprotein receptor (LDLR), liver fatty acid binding protein (LFABP), phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor (PPAR), PPAR responsive element (PPRE), all-trans-retinoic acid receptor (RAR), 9-cis-retinoic acid receptor (RXR), tumor necrosis factor xcex1 (TNFxcex1).